bims-placeb 2026-02-01 papers

bims-placeb

Biomed News

on Placental cell biology

Issue of 2026–02–01
ten papers selected by
Carlos M Guardia, National Institute of Environmental Health Sciences

Deciphering Roles of Placental Endoplasmic Reticulum Stress in Complicated Pregnancies and Beyond: The Power of Mouse Models.
Advantages, limitations, and innovative considerations for established and emerging models of human placental syncytiotrophoblast.
Altered AADAC Modulates Trophoblast Invasion and Suggests a Potential Angiogenic Regulatory Role in Severe Preeclampsia.
Ultrasound-guided selective occlusion of uteroplacental canal vessels in the mouse alters fetal growth and placental development.
Placental morphofunctional adaptations and offspring outcomes after protein restriction before and during pregnancy in mice.
Maternal High-Fat Diet Disrupts Placental Spliceosome Pathways Independent of Obesity Phenotype: Time-Series Transcriptome Analysis During Mid-to-Late Gestation in Rats.
Cannabis smoke extract disrupts trophoblast differentiation and causes mitochondrial dysfunction beyond the effects of Δ9-THC alone.
Iron Overload-Induced Ferroptosis Drives Placental Dysfunction in Preeclampsia.
From light to sound: Seeing and hearing the placenta in health and disease.
Mitochondrial Dysfunction Combined with Elevated CoQ10 Levels Specifically in Placental Cytotrophoblasts Suggests a Role for Mitophagy in Preeclampsia.

Cells. 2026 Jan 06. pii: 96. [Epub ahead of print]15(2):

Deciphering Roles of Placental Endoplasmic Reticulum Stress in Complicated Pregnancies and Beyond: The Power of Mouse Models.

Hong Wa Yung, Yat Nam Yung, Graham J Burton, D Stephen Charnock-Jones.

  Over a quarter of human pregnancies are associated with complications, including fetal growth restriction, pre-eclampsia and gestational diabetes. These are major causes of maternal and fetal morbidity and mortality, and also lead to a 3-5-fold increased risk of subsequent development of cardio-metabolic diseases. Although the mechanistic details remain elusive, a dysfunctional placenta is central to the pathophysiology of these conditions. The placenta ensures sufficient nutrient supply to the fetus without compromising maternal wellbeing. This balance is achieved by the secretion of large quantities of placental-derived peptide hormones into the maternal circulation. Consequently, the placenta is susceptible to endoplasmic reticulum (ER) stress, and we were the first to demonstrate the presence of ER stress in placentas from complicated pregnancies. The mouse placenta provides an ideal model for studying the impact of ER stress as it is composed of two distinct regions, an endocrine zone and a transport zone. Therefore, perturbation of placental endocrine function by ER stress can be generated without directly affecting its capacity for nutrient exchange. In this review, we summarise the current literature on how transgenic mouse models enhance our understanding of ER stress-mediated perturbation of placental endocrine function, and its contribution to the pathophysiology of pregnancy complications and life-long health.

Keywords:  animal model; endoplasmic reticulum stress; fetal growth restriction; placenta; pre-eclampsia; pregnancy

DOI:  https://doi.org/10.3390/cells15020096
Hum Reprod Update. 2026 Jan 27. pii: dmaf034. [Epub ahead of print]

Advantages, limitations, and innovative considerations for established and emerging models of human placental syncytiotrophoblast.

Joshua J Fisher, Ashley Williams, Farhad Soheilmoghaddam, Georgia R Kafer.

   BACKGROUND: Understanding the mechanisms that promote or hinder healthy placental development and functionality is fundamental to advancing the field of fetal and reproductive medicine. Syncytiotrophoblast (STB) are highly specialized trophoblast which develop and gain functional maturity during the first trimester of pregnancy. STB are critical to many placental functions and are often implicated in the etiology of placental pathologies. Recent advancements in cell biology have facilitated the development of innovative in vitro STB model systems. However, as the variety of available in vitro STB models grows, a critical assessment of the strengths, limitations, and appropriate applications of both established and emerging model systems is important for the field.
OBJECTIVE AND RATIONALE: With this review, we set out to compile and synthesize current knowledge on in vitro modeling of STB. Using this information, we sought to develop a balanced and thoughtful discussion regarding the use and suitability of various in vitro STB models. Our approach is grounded in a framework that considers placental development and physiology, with a specific focus on the capability of different models to recapitulate and thus enable the study of human STB differentiation, development, function, and dysfunction.
SEARCH METHOD: This review assessed published literature sourced through the PubMed database. Search terms included 'human placenta models,' 'syncytiotrophoblast models,' 'syncytiotrophoblast development,' 'trophoblast stem cells,' 'trophoblast organoids,' and 'trophoblast cell models.' The literature search was limited to English-language publications available up to August 2025.
OUTCOMES: We provide a narrative which explores the features, potential applications, and limitations of various STB models, including explant systems, immortalized trophoblast cell lines, stem cell-derived trophoblast, and a range of established and emerging 3D culture systems. Our evaluation focuses on the potential of each model to address specific research questions and highlights the challenges associated with modeling different stages of STB development and different unique aspects of STB functionality. Moreover, while remarkable progress in developing STB models has been made, no single system fully recapitulates the complex in vivo features of STB formation and function. Rather than being exhaustive, this review seeks to provide an evidence-based perspective on STB modeling in vitro which can encourage the careful consideration of the strengths and limitations of STB models.
WIDER IMPLICATIONS: This review provides an overview of the in vitro STB models currently available and a commentary of the knowledge that these systems have contributed to our understanding of STB biology. While the field has made significant progress, ongoing refinement of existing models is essential for advancing our understanding of STB and their role in both the health and dysfunction of the human placenta. By summarizing the unique adaptations and physiological changes of STB throughout gestation and aligning these with the capabilities of current models, we have developed a framework to guide future research and innovation in STB modeling. This framework is underscored by the importance of selecting models which align with specific research questions and simultaneously acknowledging the inherent limitations in extrapolating data from any in vitro systems to the biological context of the developing human placenta. By generating this discussion, we hope to contribute to the ongoing refinement of placental research methodologies and to inspire continued innovation in STB model systems.
REGISTRATION NUMBER: N/A.

Keywords:  blastoid; cytotrophoblast; model; organoid; placenta; placental development; placental dysfunction; syncytiotrophoblast; syncytium; trophoblast

DOI:  https://doi.org/10.1093/humupd/dmaf034
Int J Mol Sci. 2026 Jan 22. pii: 1103. [Epub ahead of print]27(2):

Altered AADAC Modulates Trophoblast Invasion and Suggests a Potential Angiogenic Regulatory Role in Severe Preeclampsia.

Hyo Jung An, Dae Hyun Song, Yu-Min Kim, Hyen Chul Jo, Jong Chul Baek, Juseok Yang, Ji Eun Park.

  Preeclampsia (PE) is a serious pregnancy complication characterized by hypertension and organ dysfunction. Its pathogenesis involves impaired trophoblast invasion and inadequate spiral artery remodeling; however, the underlying molecular mechanisms remain unclear. This study investigated the role of arylacetamide deacetylase (AADAC) in PE and its effects on trophoblast function by analyzing placental tissues from 30 patients with PE and 15 controls. Exploratory RNA sequencing was performed on pooled placental samples from six patients with severe PE and six controls, and AADAC expression was validated by semi-quantitative PCR and Western blotting. HTR8/SVneo cells were exposed to cobalt chloride (CoCl2) under hypoxia-mimicking conditions, and AADAC expression was manipulated by siRNA-mediated knockdown (KD) and overexpression (OE). RNA sequencing revealed increased AADAC expression in PE placentas (fold change > 2.0, raw p < 0.05). Although AADAC mRNA levels were elevated in PE tissues, protein levels were reduced. CoCl2 exposure was associated with increased expression of AADAC and hypoxia-inducible factor-1 alpha (HIF-1α). Under hypoxia-mimicking conditions, AADAC silencing was associated with increased trophoblast invasion and tube formation, whereas AADAC overexpression reduced tube formation without significantly affecting invasion. These findings suggest that dysregulated, hypoxia-responsive AADAC expression influences trophoblast invasive and angiogenic behavior in preeclampsia.

Keywords:  arylacetamide deacetylase; placenta; preeclampsia; trophoblast

DOI:  https://doi.org/10.3390/ijms27021103
Am J Physiol Heart Circ Physiol. 2026 Jan 27.

Ultrasound-guided selective occlusion of uteroplacental canal vessels in the mouse alters fetal growth and placental development.

Sarah K Debebe, Anum Rahman, Taylor DeYoung, Lindsay S Cahill, W Tony Parks, Christopher K Macgowan, John C Kingdom, John G Sled.

  Placental insufficiency associated with impaired uteroplacental blood flow is the leading cause of human fetal growth restriction. While preclinical studies have examined the effects of global reductions in uterine blood flow, the downstream consequences of a focal disruption in flow remains unknown. We investigate how murine maternal canal occlusion(s) impacts placental development and fetal growth. Pregnant CD-1 mice at embryonic (E) day 15.5 underwent abdominal surgery to exteriorize the uterus. Under ultrasound guidance, zero, one or two of the, typically three, placental canals were microinjected with an embolizing agent. Survival at term (E18.5) was 81% for shams, 62% for single embolized, and 24% for the double embolized. Surviving double embolized fetuses weighed significantly less than both internal and external controls. The brain-to-liver volume ratio was significantly elevated in the singles and doubles versus controls (p = 0.00537, p = 0.00861) and shams (p = 0.01207, p = 0.017738). Placental histopathology, and 3D MRI confirmed, a reduction in junctional zone volume and significantly higher whole placenta-to-junctional zone volume ratio in the single embolized cohort (9.66, 95% CI [8.23-11.1]) compared to naïve controls and shams (6.21, 95% CI [4.79-7.63], p = 0.0298; (6.20, 95% CI [4.71-7.70], p = 0.00394, respectively). Canal occlusion resulted in impaired fetal growth and altered placental morphology yet did not cause focal placental infarction typical of impaired uteroplacental blood flow in humans. This placental model of fetal growth restriction may be amenable to testing new intervention strategies aimed at supporting fetal growth when placental function is impaired.

Keywords:  Fetal growth restriction; Magnetic resonance imaging; Mouse models; Placental insufficiency; Ultrasound biomicroscopy

DOI:  https://doi.org/10.1152/ajpheart.00603.2025
J Nutr Biochem. 2026 Jan 25. pii: S0955-2863(26)00027-6. [Epub ahead of print] 110285

Placental morphofunctional adaptations and offspring outcomes after protein restriction before and during pregnancy in mice.

Fernando Felicioni, José Andrés Nivia-Riveros, Andre Lucas Caldeira-Brant, Thais de Mérici Domingues E Paula, Lucas Carvalho Cardoso, Camila Ferreira Sales, Julia Meireles Nogueira, Ana Maria Alvarenga Fagundes, Elizete Rizzo, Hélio Chiarini-Garcia, Erika Cristina Jorge, Enrrico Bloise, Fernanda Radicchi Campos Lobato de Almeida.

  Proper fetal development depends on maternal nutrition. We investigated the placental morphofunctional adaptations to a low-protein diet, and their impact on fetal and newborn outcomes. Swiss mice were fed either normal (NPD, 20% crude protein, n=29) or low protein (LPD, 8% crude protein, n=26) diets two weeks before and throughout pregnancy. Dams were euthanized at gestational days (GD) 7.5 and 17.5 for morphological and molecular evaluations. No biometrical or histological alterations were observed in embryonic sites in both GDs. However, LPD placentae exhibited 14.2% increase in maternal sinusoid and 8% reduction in fetal vessel proportions (P<0.05), without significant changes in cellular proliferation, or apoptosis. Placental gene expression analysis varied according to uterine location: LPD placentae near the ovary exhibited downregulation of Fatp4, Mtor, and Kiss1, while Stat3 was upregulated (P<0.05); in the middle third of the uterine horn, Snat1 and Kiss1 were upregulated, while Snat4 was downregulated (P<0.05); and close to the uterine body, Igf2r was downregulated, whereas Snat1 and Kiss1r were upregulated (P<0.05), suggesting region-specific compensatory mechanisms. LPD placentae and fetuses were lighter and exhibited higher brain-to-liver weight ratio in both genders (P<0.05). Maternal LPD intake disproportionately affected male fetuses, which presented higher placental efficiency (P<0.05), yet failed to reach their full growth potential. At birth, although newborn size was not affected by LPD, liver weights were lower and brain-to-liver weight ratios remained higher (P<0.05), particularly in males. Maternal LPD induces region-specific placental adaptations that partially compensate for nutrient restriction, yet still impair fetal growth, particularly in male offspring.

Keywords:  DOHaD; birth weight; fetal growth; low protein diet; placental adaptation; placental histomorphometry

DOI:  https://doi.org/10.1016/j.jnutbio.2026.110285
Biol Reprod. 2026 Jan 28. pii: ioag023. [Epub ahead of print]

Maternal High-Fat Diet Disrupts Placental Spliceosome Pathways Independent of Obesity Phenotype: Time-Series Transcriptome Analysis During Mid-to-Late Gestation in Rats.

Xiaohan Du, Yuchen Wei, Zhiyin Le, Hongliang Wang, Zhaoyang Chen, Huanling Yu, Xiaxia Cai.

   BACKGROUND AND OBJECTIVE: Maternal obesity is known to adversely affect fetal development, with placental transcriptional dysregulation being one of the key mechanisms. However, the effect of a maternal high-fat diet (HFD) on dynamic placental gene expression, particularly in the context of obesity propensity, remains poorly understood. This study aimed to investigate the impact of a maternal HFD on time-dependent placental transcriptome alterations, with a focus on identifying key dysregulated pathways during mid-to-late gestation in rats.
METHODS: Female Sprague-Dawley rats were fed either a high-fat diet (HFD) or control chow (CC) diet before and during pregnancy. HFD-treated rats were categorized into obese-prone (OP) and obese-resistant (OR) groups based on pre-pregnancy weight. Maternal and fetal characteristics, as well as fetal outcomes, were recorded at gestational days (GD) 14.5, 17.5, and 19.5. Plasma cytokine levels were also measured. RNA sequencing (RNA-seq) was used to compare the transcriptomes of the three groups at GD 14.5, GD 17.5, and GD 19.5.
RESULTS: At GD 14.5, OP and OR groups showed significantly lower fetal body weight, placental weight, and efficiency compared to the CC group, with these measures increasing significantly by GD 17.5. Concurrently, RNA-seq time-series analysis revealed a significant dysregulation of the spliceosome pathway in the OR group and the parathyroid hormone synthesis pathway in the OP group during mid-to-late gestation. Specifically, 19 out of 229 annotated spliceosome genes were differentially expressed in the OR group. These transcriptomic findings were robustly validated by qPCR, which confirmed the upregulation of Sf3a1 and Sart1 in both the OR and OP groups at GD 14.5, while Sf3a2, Sf3b4, and Rbm22 were specifically elevated in the OP group.
CONCLUSION: Maternal high-fat diet disrupts placental transcriptome dynamics during mid-to-late gestation, particularly affecting spliceosome pathways, regardless of maternal obesity phenotype, contributing to placental dysfunction and adverse fetal outcomes. The observed time-dependent divergences highlight the need for phenotype- and gestational stage-specific interventions to mitigate developmental risks associated with maternal HFD.

Keywords:  Maternal high-fat diet; placental transcriptome; spliceosome pathways

DOI:  https://doi.org/10.1093/biolre/ioag023
Sci Rep. 2026 Jan 26.

Cannabis smoke extract disrupts trophoblast differentiation and causes mitochondrial dysfunction beyond the effects of Δ9-THC alone.

Cristina Monaco, Mahek Minhas, Tina Podinic, Joshua P Nederveen, Amica-Mariae Lucas, Thane Tomy, Gregg T Tomy, Alison C Holloway, Sandeep Raha.

  Smoking cannabis remains the most common mode of consumption amongst pregnant people, yet the effects on placentation remain poorly understood. While prior studies have focused on exposure to single components of cannabis (i.e., Δ9-THC and CBD), this approach overlooks the complex toxicology and pharmacology of cannabis smoke exposure. In this study, we used an in vitro model of human trophoblast differentiation to investigate the impact of CaSE (cannabis smoke extract) compared to Δ9-THC. We show that CaSE, but not Δ9-THC induces CYP1A1 expression, a marker of exposure to combustion by-products. CaSE reduced hCG protein levels and syncytin-1 gene expression, suggesting impaired syncytialization. Lower concentrations of CaSE (1%, 2.5%) elevated reactive oxygen species without impacting membrane potential, whereas higher concentrations (5%, 10%) disrupted mitochondrial respiration, indicating dose-dependent bioenergetic dysfunction. Antioxidant genes, superoxide dismutase 1 and 2, were distinctly altered indicating the divergence in oxidative stress responses. Interestingly, CB1R antagonism rescued the effects of Δ9-THC exposure, but not CaSE-mediated effects on differentiation markers. Since most cannabis users consume cannabis by smoking, and smoke exposure differs from single components (Δ9-THC), it is important that preclinical models consider smoking when evaluating the impacts of cannabis use during pregnancy.

Keywords:  Cannabis smoke extract; Endocannabinoid signaling; Mitochondrial dysfunction; Oxidative stress; Placental development; Trophoblast differentiation

DOI:  https://doi.org/10.1038/s41598-026-36939-8
Hypertension. 2026 Jan 29.

Iron Overload-Induced Ferroptosis Drives Placental Dysfunction in Preeclampsia.

Yike Yang, Haoyu Zuo, Xiaojuan Ma, Wei Chen, Mengxing Sun, Qianqian Xiang, Yuan Wei, Yangyu Zhao, Hongbo Qi, Tong Liu.

   BACKGROUND: Preeclampsia, a life-threatening hypertensive disorder of pregnancy, has been linked to iron dysregulation, though mechanistic insights remain limited.
METHODS: We integrated clinical data, a reduced uterine perfusion pressure mouse model, in vitro trophoblast cell experiments, and placental organoids derived from patients with preeclampsia. Iron metabolism was assessed via mass spectrometry, quantitative polymerase chain reaction, Peris' Prussian blue staining and immunohistochemistry. Ferroptosis markers and iron transporters were analyzed. Interventions included the iron chelator deferoxamine, antioxidant MitoQ, ferroptosis inhibitor Fer-1 (ferrostatin-1), and the apoptosis inhibitor Z-VAD.
RESULTS: Patients with preeclampsia exhibited elevated hemoglobin, ferritin, and serum iron levels from the second trimester, alongside placental iron overload. Single-cell/nucleus RNA sequencing revealed dysregulated iron transporters (TFRC↑, DMT1↑, FPN↓) in preeclampsia trophoblasts. Iron overload induced ferroptosis and apoptosis in trophoblasts, evidenced by increased lipid peroxidation (4HNE↑, Gpx4↓), ROS, Tunnel staining positive and cell death, while suppressing PlGF and progesterone secretion. Both deferoxamine and MitoQ rescued these effects in vitro (similar to Ferr-1) and in preeclampsia-derived organoids. The reduced uterine perfusion pressure model confirmed the preservation of iron dyshomeostasis and ferroptosis in preeclamptic placentas, while oral administration of MitoQ was found to reduce 4-hydroxynonenal and malondialdehyde expression in placenta.
CONCLUSIONS: Our findings reveal that iron overload and subsequent ferroptosis contribute to placental damage in preeclampsia, suggesting that iron metabolism dysregulation is a critical feature of the disease. This highlights the need to reevaluate iron supplementation protocols in high-risk pregnancies and to consider individualized iron management strategies that balance maternal-fetal iron requirements while minimizing oxidative stress.

Keywords:  antioxidant; deferoxamine; ferroptosis; lipid peroxidation; oxidative stress

DOI:  https://doi.org/10.1161/HYPERTENSIONAHA.125.26344
Sci Adv. 2026 Jan 30. 12(5): eaed2184

From light to sound: Seeing and hearing the placenta in health and disease.

Donghyun Lee, Jiwoong Kim, Jinseok Heo, Hyunseo Jeon, Shiyang Chang, Wonseok Choi, Chulhong Kim, Zhifen Yang.

The placenta is a pregnancy-specific organ, functioning as the maternal-fetal interface and mediating essential processes including exchange, protection, and endocrine regulation. Placental abnormalities contribute to the pathophysiology, onset, progression, and prognosis of major perinatal disorders, making imaging modalities that enable their detection and monitoring crucial. Ultrasound (US) imaging is the principal modality for placental imaging, providing structural assessment with B-mode and blood flow evaluation with Doppler mode. Furthermore, advanced techniques such as 3D power Doppler, quantitative US, and shear-wave elastography expand the capabilities of placental US imaging. Photoacoustic (PA) imaging enables observation of the optical properties of endogenous chromophores (e.g., hemoglobin) with high spatial resolution and measures blood oxygenation, a key factor in placental dysfunction, offering substantial value for placental imaging. In this review, we cover US/PA imaging techniques for placental imaging, including preclinical and clinical studies. In addition, by considering current limitations and potential solutions, we suggest future trajectories for the advancement of US/PA imaging in this field.

DOI: https://doi.org/10.1126/sciadv.aed2184
Biology (Basel). 2026 Jan 13. pii: 139. [Epub ahead of print]15(2):

Mitochondrial Dysfunction Combined with Elevated CoQ10 Levels Specifically in Placental Cytotrophoblasts Suggests a Role for Mitophagy in Preeclampsia.

Jessica Ábalos-Martínez, Francisco Visiedo, María Victoria Cascajo-Almenara, Celeste Santos-Rosendo, Victoria Melero-Jiménez, Carlos Santos-Ocaña, Luis Vázquez-Fonseca, Fernando Bugatto.

  Preeclampsia is a serious pregnancy disorder of unknown etiology. One of its cellular hallmarks is increased mitochondrial dysfunction in placental tissue. Further investigation into this aspect may help elucidate the molecular basis of preeclampsia. A total of 24 pregnant women who delivered by cesarean section participated in the study: n = 13 controls and n = 11 diagnosed with preeclampsia. Maternal blood samples were collected to assess the biochemical profile, and demographic and clinical data were recorded. Placental trophoblast samples were processed to isolate mitochondria and perform molecular biology assays. Women with preeclampsia exhibited the characteristic clinical features of the disease, along with biochemical alterations consistent with an inflammatory process. A significant decrease (73%) in mitochondrial DNA (mtDNA) copy number in trophoblastic tissue and a reduction in citrate synthase (CS) activity (-51%) in cytotrophoblast mitochondria-enriched fractions were observed in preeclampsia, indicating mitochondrial dysfunction accompanied by a loss of functional mitochondrial mass. In addition, we detected a marked decrease in MnSOD levels (-32%), together with an increase in the LC3II/LC3I ratio (47%) in cytotrophoblast mitochondria-enriched fractions, supporting the presence of mitochondrial alterations and suggesting the possible activation of mitophagy specifically in this cell type. Moreover, coenzyme Q10 (CoQ10) levels were elevated by 31% in trophoblastic villi. A pronounced 2.5-fold increase in CoQ10 normalized to CS activity (CoQ10/CS) was detected specifically in cytotrophoblasts from preeclamptic placentas. Importantly, we did not observe these alterations in the syncytiotrophoblast. In conclusion, preeclampsia is associated with mitochondrial dysfunction and increased CoQ10 levels normalized to CS activity, specifically in cytotrophoblast mitochondria, with findings being consistent with a possible involvement of mitophagy in this cell type. These findings suggest that cytotrophoblast mitochondrial metabolism may be more affected in preeclampsia compared with syncytiotrophoblasts, and that CoQ10 accumulation together with the possible activation of mitophagy may represent cellular defense mechanisms. Due to the limitations of the study, it should be considered exploratory and hypothesis-generating, and its results should be regarded as preliminary.

Keywords:  coenzyme Q10; cytotrophoblast; mitochondria; mitophagy; preeclampsia

DOI:  https://doi.org/10.3390/biology15020139